FBXO2-mediated KPTN ubiquitination promotes amino acid-dependent mTORC1 signaling and tumor growth

Jianfang Gao; Jina Qing; Xianglong Li; Yuxuan Luo; Lingwen Huang; Hongxia Li; Huan Zhang; Jiao Zhang; Pei Xiao; Jinsong Li; Tingting Li; Shanping He

doi:10.1172/JCI195031

¹Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulatio, Institute of Interdisciplinary Studies, College of Life Sciences, Hunan Normal University, Changsha, China

²Department of Spine Surgery, The Third Xiangya Hospital of Central South University, Changsha, China

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¹Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulatio, Institute of Interdisciplinary Studies, College of Life Sciences, Hunan Normal University, Changsha, China

²Department of Spine Surgery, The Third Xiangya Hospital of Central South University, Changsha, China

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¹Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulatio, Institute of Interdisciplinary Studies, College of Life Sciences, Hunan Normal University, Changsha, China

²Department of Spine Surgery, The Third Xiangya Hospital of Central South University, Changsha, China

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¹Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulatio, Institute of Interdisciplinary Studies, College of Life Sciences, Hunan Normal University, Changsha, China

²Department of Spine Surgery, The Third Xiangya Hospital of Central South University, Changsha, China

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¹Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulatio, Institute of Interdisciplinary Studies, College of Life Sciences, Hunan Normal University, Changsha, China

²Department of Spine Surgery, The Third Xiangya Hospital of Central South University, Changsha, China

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¹Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulatio, Institute of Interdisciplinary Studies, College of Life Sciences, Hunan Normal University, Changsha, China

²Department of Spine Surgery, The Third Xiangya Hospital of Central South University, Changsha, China

Find articles by Li, H. in: PubMed | Google Scholar

¹Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulatio, Institute of Interdisciplinary Studies, College of Life Sciences, Hunan Normal University, Changsha, China

²Department of Spine Surgery, The Third Xiangya Hospital of Central South University, Changsha, China

Find articles by Zhang, H. in: PubMed | Google Scholar

¹Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulatio, Institute of Interdisciplinary Studies, College of Life Sciences, Hunan Normal University, Changsha, China

²Department of Spine Surgery, The Third Xiangya Hospital of Central South University, Changsha, China

Find articles by Zhang, J. in: PubMed | Google Scholar

¹Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulatio, Institute of Interdisciplinary Studies, College of Life Sciences, Hunan Normal University, Changsha, China

²Department of Spine Surgery, The Third Xiangya Hospital of Central South University, Changsha, China

Find articles by Xiao, P. in: PubMed | Google Scholar

¹Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulatio, Institute of Interdisciplinary Studies, College of Life Sciences, Hunan Normal University, Changsha, China

²Department of Spine Surgery, The Third Xiangya Hospital of Central South University, Changsha, China

Find articles by Li, J. in: PubMed | Google Scholar

¹Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulatio, Institute of Interdisciplinary Studies, College of Life Sciences, Hunan Normal University, Changsha, China

²Department of Spine Surgery, The Third Xiangya Hospital of Central South University, Changsha, China

Find articles by Li, T. in: PubMed | Google Scholar

¹Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulatio, Institute of Interdisciplinary Studies, College of Life Sciences, Hunan Normal University, Changsha, China

²Department of Spine Surgery, The Third Xiangya Hospital of Central South University, Changsha, China

Find articles by He, S. in: PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI195031.
Copyright © 2025, Gao et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published December 16, 2025 - Version history

Mechanistic target of rapamycin complex 1 (mTORC1) is a master controller of cell growth and its dysregulation is associated with cancer. KICSTOR, a complex comprising KPTN, ITFG2, C12orf66, and SZT2, functions as a critical negative regulator of amino acid-induced mTORC1 activation. However, the regulatory mechanisms governing KICSTOR remain largely unclear. In this study, we identify FBXO2 as a key modulator of amino acid-dependent mTORC1 signaling. Mechanistically, FBXO2 colocalizes and directly interacts with KPTN via its F-box-associated domain, promoting K48- and K63-linked polyubiquitination of KPTN at lysine residues 49, 67, 262, and 265. FBXO2-mediated KPTN ubiquitination disrupts its interaction with ITFG2 and SZT2, while enhancing its interaction with C12orf66, thereby impairing the ability of KICSTOR to recruit the GATOR1 complex to the lysosomal surface. Notably, FBXO2 protein levels are substantially upregulated in liver cancer patients and FBXO2-mediated KPTN ubiquitination facilitates the progression of hepatocellular carcinoma (HCC). These results reveal a key regulatory mechanism of the mTORC1 signaling and highlight FBXO2 and KPTN ubiquitination as therapeutic targets for HCC treatment.

Version 1 (December 16, 2025): In-Press Preview

FBXO2-mediated KPTN ubiquitination promotes amino acid-dependent mTORC1 signaling and tumor growth

Jianfang Gao,¹ Jina Qing,¹ Xianglong Li,¹ Yuxuan Luo,¹ Lingwen Huang,¹ Hongxia Li,¹ Huan Zhang,¹ Jiao Zhang,¹ Pei Xiao,¹ Jinsong Li,² Tingting Li,¹ and Shanping He¹

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FBXO2-mediated KPTN ubiquitination promotes amino acid-dependent mTORC1 signaling and tumor growth

Jianfang Gao,1 Jina Qing,1 Xianglong Li,1 Yuxuan Luo,1 Lingwen Huang,1 Hongxia Li,1 Huan Zhang,1 Jiao Zhang,1 Pei Xiao,1 Jinsong Li,2 Tingting Li,1 and Shanping He1

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Jianfang Gao,¹ Jina Qing,¹ Xianglong Li,¹ Yuxuan Luo,¹ Lingwen Huang,¹ Hongxia Li,¹ Huan Zhang,¹ Jiao Zhang,¹ Pei Xiao,¹ Jinsong Li,² Tingting Li,¹ and Shanping He¹